1. Field of the Invention
The present invention relates to preparation of microparticles. More particularly, the present invention relates to microparticles having improved flowability, and to a method for the preparation of such microparticles.
2. Related Art
Various methods are known by which compounds can be encapsulated in the form of microparticles. It is particularly advantageous to encapsulate a biologically active or pharmaceutically active agent within a biocompatible, biodegradable wall-forming material (e.g., a polymer) to provide sustained or delayed release of drugs or other active agents. In these methods, the material to be encapsulated (drugs or other active agents) is generally dissolved, dispersed, or emulsified in a solvent containing the wall forming material. Solvent is then removed from the microparticles to form the finished microparticle product.
An example of a conventional microencapsulation process is disclosed in U.S. Pat. No. 3,737,337 wherein a solution of a wall or shell forming polymeric material in a solvent is prepared. The solvent is only partially miscible in water. A solid or core material is dissolved or dispersed in the polymer-containing solution and, thereafter, the core-material-polymer-containing solution is dispersed in an aqueous liquid that is immiscible in the organic solvent in order to remove solvent from the microparticles.
Tice et al. in U.S. Pat. No. 4,389,330 describe the preparation of microparticles containing an active agent by using a two-step solvent removal process. In the Tice et al. process, the active agent and the polymer are dissolved in a solvent. The mixture of ingredients in the solvent is then emulsified in a continuous-phase processing medium that is immiscible with the solvent. A dispersion of microparticles containing the indicated ingredients is formed in the continuous-phase medium by mechanical agitation of the mixed materials. From this dispersion, the organic solvent can be partially removed in the first step of the solvent removal process. After the first stage, the dispersed microparticles are isolated from the continuous-phase processing medium by any convenient means of separation. Following the isolation, the remainder of the solvent in the microparticles is removed by extraction. After the remainder of the solvent has been removed from the microparticles, they are dried by exposure to air or by other conventional drying techniques.
Another conventional method of microencapsulating an agent to form a microencapsulated product is disclosed in U.S. Pat. No. 5,407,609. This method includes: (1) dissolving or otherwise dispersing one or more agents (liquids or solids) in a solvent containing one or more dissolved wall-forming materials or excipients (usually the wall-forming material or excipient is a polymer dissolved in a polymer solvent); (2) dispersing the agent/polymer-solvent mixture (the discontinuous phase) into a processing medium (the continuous phase which is preferably saturated with polymer solvent) to form an emulsion; and (3) transferring all of the emulsion immediately to a large volume of processing medium or other suitable extraction medium, to immediately extract the solvent from the microdroplets in the emulsion to form a microencapsulated product, such as microcapsules or microspheres.
U.S. Pat. No. 5,650,173 discloses a process for preparing biodegradable, biocompatible microparticles comprising a biodegradable, biocompatible polymeric binder and a biologically active agent, wherein a blend of at least two substantially non-toxic solvents, free of halogenated hydrocarbons, are used to dissolve both the agent and the polymer. The solvent blend containing the dissolved agent and polymer is dispersed in an aqueous solution to form droplets. The resulting emulsion is added to an aqueous extraction medium preferably containing at least one of the solvents of the blend, whereby the rate of extraction of each solvent is controlled, whereupon the biodegradable, biocompatible microparticles containing the biologically active agent are formed. Active agents suitable for encapsulation by this process include, but are not limited to, norethindrone, risperidone, and testosterone, and a preferred solvent blend is one comprising benzyl alcohol and ethyl acetate.
U.S. Pat. No. 5,654,008 describes a microencapsulation process that uses a static mixer. A first phase, comprising an active agent and a polymer, and a second phase are pumped through a static mixer into a quench liquid to form microparticles containing the active agent.
The documents described above all disclose methods that can be used to prepare microparticles that contain an active agent. However, flowability of these microparticles immediately after processing and recovery may be poor. Good flowability is characterized by steady, controlled flow similar to dry sand. Poor flowability, on the other hand, is characterized by uncontrolled, erratic flow similar to wet sand. In this case the entire bulk tries to move in a solid mass. This last condition is termed “floodable” flow and is most characteristic of cohesive, sticky powders. Flowability is an important consideration in large-scale processing when invariably these powders or microparticles must be moved from place to place. It is a particularly important consideration when using automated filling equipment where material must flow from a hopper. Microparticles having poor flow properties tend to “arch” or “bridge” and then may “rat hole” or stop completely when discharged from the hopper. In this case further processing must be abandoned. None of the documents discussed above discloses a specific method for preparing microparticles that have improved flowability.
Notably, none of the documents discussed above address the problems of improved flowability for microparticles containing an active agent, or for microparticles with no encapsulated active agent. Microparticles devoid of active agent may be referred to herein as “placebo microparticles.” Placebo microparticles are used in clinical studies of microparticles containing an active agent, such as in blinded clinical studies. As with microparticles containing an active agent, it is important to control the flowability of placebo microparticles to process them in automated powder filling equipment. Moreover, it is preferable that the methods of manufacture and the quality characteristics of the placebo microparticles are similar to the drug-loaded microparticles to avoid noticeable differences in blinded clinical studies.
Thus, there is a need in the art for a method for preparing microparticles having improved flowability. There is a further need in the art for a method for preparing microparticles with improved flowability so that such microparticles can be processed in automated powder filling equipment. There is yet a further need in the art for preparing microparticles with improved flowability that is applicable to both microparticles containing an active agent, and to placebo microparticles. The present invention, the description of which is fully set forth below, solves the need in the art for such methods.